Subanesthetic Ketamine Infusions for Depressive Symptoms in Intensive Care Unit Patients

Depressive symptoms are clinically relevant among patients with critical illness and may be exacerbated by acute illness, pain, immobility, sleep disruption, loss of autonomy, and prolonged hospitalization. These symptoms may negatively affect recovery, participation in care, treatment adherence, quality of life, and outcomes after critical illness.

Ketamine is an N-methyl-D-aspartate receptor antagonist with rapid antidepressant effects when administered at subanesthetic doses. In non-ICU populations, intravenous ketamine has been associated with early improvement in depressive symptoms. However, its efficacy and safety for depressive symptoms developing during critical illness remain uncertain.

KID-ICU is a Phase II randomized, double-blind, placebo-controlled, multicenter clinical trial with two parallel groups and 1:1 allocation. Eligible participants will be adult ICU patients with moderate-to-severe depressive symptoms, defined as a Patient Health Questionnaire-9 (PHQ-9) score of 10 or greater after 6 or more days of ICU admission. The PHQ-9 will be used to measure depressive symptom severity and not as a standalone diagnostic instrument for major depressive disorder.

Participants assigned to the ketamine group will receive intravenous ketamine at 0.5 mg/kg, with a maximum dose of 60 mg per infusion, administered over 60 minutes once daily for 2 consecutive days. Participants assigned to the placebo group will receive intravenous normal saline in an identical volume, appearance, and infusion duration. Study medication will be prepared by the research pharmacy in indistinguishable infusion bags.

Participants, care providers, investigators, and outcome assessors will remain blinded to treatment assignment. Only authorized unblinded research pharmacy personnel and the trial statistician responsible for generating or maintaining the allocation sequence will have access to treatment assignments. Emergency unblinding will be available through a predefined institutional procedure when knowledge of the assigned treatment is required for the clinical management of a serious or life-threatening event.

Randomization will be stratified by participating ICU site and implemented through the Research Electronic Data Capture randomization module. Treatment allocation will remain concealed until the database is locked, except when emergency unblinding is required.

Participants will undergo continuous clinical monitoring during and after each infusion, including heart rate, cardiac rhythm, blood pressure, peripheral oxygen saturation, respiratory status, and mental status. Adverse events will be assessed before, during, and after each infusion using clinical monitoring and the Ketamine Side Effect Tool. An infusion may be temporarily interrupted or permanently discontinued because of clinically significant hypertension, tachycardia, bradycardia, arrhythmia, respiratory deterioration, deterioration in consciousness, severe agitation, psychotic symptoms, or another serious adverse event according to prespecified criteria and investigator judgment.

Study assessments will be performed at baseline before the first infusion, before the second infusion, 24 hours after the second scheduled infusion, and at Days 7, 14, and 30 after the second scheduled infusion. Telephone follow-up will be permitted for participants discharged before completion of follow-up, using the same standardized outcome assessment procedures.

Depressive symptoms will be assessed with the PHQ-9. Anxiety and depressive symptoms will be assessed using the anxiety and depression subscales of the Hospital Anxiety and Depression Scale. Global clinical severity and improvement will be assessed using the Clinical Global Impression-Severity and Clinical Global Impression-Improvement scales.

The primary efficacy outcome is the change in PHQ-9 total score from baseline to Day 14 after the second scheduled infusion. Secondary outcomes include the longitudinal trajectory of PHQ-9 scores through Day 30, clinically meaningful PHQ-9 response at Day 14, longitudinal changes in Hospital Anxiety and Depression Scale subscale scores, Clinical Global Impression scores, prespecified treatment-emergent safety events, time to ICU discharge alive, time to hospital discharge alive, and all-cause mortality within 30 days after randomization.

The primary efficacy analysis will follow the intention-to-treat principle and compare PHQ-9 scores at Day 14 between treatment groups, adjusting for baseline PHQ-9 score and participating site. The treatment effect will be reported with a 95 percent confidence interval. Longitudinal PHQ-9 scores will be evaluated using a mixed-effects model including treatment group, categorical assessment time, and the treatment-by-time interaction. Time-to-discharge outcomes will account for death as a competing event. Secondary analyses will be considered exploratory.

All data will be collected prospectively using the Research Electronic Data Capture platform. Bedside assessments may initially be documented on paper source forms and subsequently transcribed into the electronic database. The planned sample size is 50 participants, with 25 participants assigned to each treatment group.

**Inclusion Criteria:**

• Age 18 to 99 years.
• Male or female.
• Admission to an intensive care unit for 6 or more days at the time of screening.
• Moderate to severe depressive symptoms, defined as a Patient Health Questionnaire-9 score of 10 or greater at screening.
• Ability to provide informed consent.

**Exclusion Criteria:**

• History of psychosis or hallucinations, as assessed by review of the electronic medical record and patient interview during screening.
• History of prolonged QT interval.
• History of dementia.
• History of major depressive disorder before the current intensive care unit admission.
• History of psychiatric diagnosis, including dissociative disorder, primary psychotic disorder, mania with psychosis, pervasive developmental disorder, cognitive disorder, or anorexia nervosa.
• Known allergy to ketamine or diphenhydramine.
• History of increased intracranial pressure, hypertensive hydrocephalus, or increased intraocular pressure.
• Hemodynamic instability at the time of screening, defined as peripheral oxygen saturation <95%, systolic blood pressure <90 mmHg or >180 mmHg, heart rate <50 or >120 beats/min, or respiratory rate <10 or >30 breaths/min.
• Patient refusal to participate or to provide informed consent.
• Pregnancy, postpartum period within 2 months, or breastfeeding.
• Presence of intracranial mass or vascular lesion.
• Altered mental status precluding informed consent.
• Body weight >115 kg or <45 kg.
• Active psychosis.
• Current treatment with medications that may interfere with the N-methyl-D-aspartate receptor system, including lamotrigine, acamprosate, memantine, riluzole, or lithium.
• Current treatment with aminophylline or theophylline.
• Active substance withdrawal or use of hallucinogens, including cannabis, in the past month, as determined by clinical interview and urine drug screening.